Life Cycle and Aquatic Biodegradation Assessments of Pharmaceutical Excipients: Development of a Selection Guide for Drug Formulations

Pharmaceutical excipients are essential components of drug formulations, yet their environmental impacts have received less attention than those of active pharmaceutical ingredients (APIs). A major group of formulation excipients are polymers, which can be either water-soluble or water-insoluble and are referred to as polymeric excipients (PEx). The environmental fate of PEx is crucially determined by its biodegradability. However, standard OECD 301 ready biodegradability tests were not originally designed for polymers. Therefore, these tests must be adapted further to establish their applicability to polymers. In addition, emissions throughout their life cycle must be considered to obtain a comprehensive picture of their environmental impact. This dissertation aims to address these data gaps by presenting four complementary publications (publications 1-4, P1-4). These publications systematically evaluated the biodegradability and life-cycle impacts of excipients, providing a foundation for the safe and sustainable design of PEx (“Benign-by-Design”, BbD). A stepwise approach based on OECD 301D and 301F tests was used to systematically evaluate the biodegradability of PEx, incorporating progressively increasing levels of microbial density and diversity (P1-3). Substantial variability in degradation outcomes across different PEx and test conditions was observed. For instance, synthetic polymers such as polyvinyl pyrrolidone and polymethyl methacrylate showed no measurable degradation, most likely because they lack the oxidizable or hydrolysable groups necessary for microbial degradation (P2). Similarly, cellulose-based excipients with high degrees of substitution (DS) and molar substitution (MS) showed no biodegradation, suggesting that extensive derivatization hinders enzymatic accessibility (P1). Poloxamer 188 (a block copolymer) also showed no biodegradation under any of the test conditions; the ratio of polyethylene glycol (PEG) to polypropylene glycol (PPG) appears to influence its biodegradability (P3). Even when using a stepwise approach that incorporated increasing microbial diversity and density, there was still no measurable biodegradation of these non-biodegradable compounds. In contrast, other PEx, such as polyethylene glycol (PEG) and polyvinyl alcohol (PVA), were readily biodegradable when tested with inocula of sufficient microbial diversity and density. These results underscored the importance of adequate microbial biomass for effectively initiating and monitoring biodegradation within a 28-day timeframe. Some PEx displayed partial biodegradability, with degradation ranging from 20 to 59 %, which is below the OECD 301 "readily biodegradable" threshold of 60 %. For example, polysorbate 80 showed 30-45 % degradation, producing ethoxylated sorbitan residues that persisted as "dead-end" transformation products (P3). Together, P1-3 revealed that the biodegradation outcomes are influenced by the complex interplay between molecular structure, microbial adaptation, and test conditions. In addition, findings of P1-3 provided valuable empirical data that advance scientific understanding and regulatory discourse in two key areas. First, OECD 301 screening tests can be technically applied to polymeric substances, however, their limitations must be recognized: Inocula derived from secondary effluent frequently underestimated biodegradation, whereas activated sludge, with higher microbial density and diversity, enabled detection of biodegradation. This emphasizes the importance of optimizing test protocols for PEx to ensure meaningful and representative results. Second, the binary pass/fail criteria typically employed in OECD 301 tests are inadequate for capturing the full range of biodegradation behaviors of PEx observed. To overcome this limitation, a graded "traffic-light" classification system has been developed that categorizes substances as non-biodegradable, slightly biodegradable, moderately biodegradable, or readily biodegradable (P1-3). This classification is based on biodegradation curve patterns, mineralization percentages and mechanistic insights derived from structure-biodegradability relationships, enabling a more accurate interpretation of screening-level results. P4 emphasized the need to move away from single-parameter assessments of environmental risk, such as biodegradability, and adopt a systems-level approach in line with the “Safe and Sustainable by Design” framework. Life-cycle assessment results showed that energy-related emissions were the main contributor to the overall impact of most excipients, due to electricity and thermal energy use during manufacturing. Process-related emissions also made a significant contribution to the overall environmental impact of certain excipients, such as the release of ozone-depleting methyl chloride from chemically methylated cellulose derivatives. In case of bio-based excipients, both the use of fertilizers, which caused eutrophication, and water consumption for irrigation contributed significantly to the overall environmental impact. These multiple emission sources must be considered because they demonstrate that environmental impacts cannot be inferred from biodegradability alone. The different excipients involved can result in trade-offs between production impact and biodegradability. This highlights the importance of holistic assessments in sustainable decision-making. For instance, although lactose showed high biodegradability, it had a significant production footprint. In contrast, Eudragit derivatives exhibited lower production impacts but poor biodegradability. A key outcome of this research was the development of the Excipient Selection Guide, which translates these insights into practical guidance. This tool combines biodegradability and life-cycle data to enable the informed selection of excipients that have a lower overall environmental impact. It supports the development of safer and more sustainable pharmaceuticals following the BbD concept. Together, P1-P4 provided the first systematic evaluation of pharmaceutical excipients by integrating biodegradability with life-cycle considerations. The Excipient Selection Guide may be used in the early stages of pharmaceutical development to select or develop more sustainable excipients. As excipients are used universally across the pharmaceutical industry, reducing their environmental impact using this tool has significant implication for the sector. Furthermore, excipients are used in many other sectors, including chemistry, food, cosmetics, personal care and household products. This broadens the guide’s applicability and its potential to enhance environmental sustainability across industries.

Pharmazeutische Hilfsstoffe sind wesentliche Bestandteile von Arzneimitteln. Ihre Umweltauswirkungen wurden jedoch bisher weniger häufig untersucht als die von Wirkstoffen. Eine wichtige Gruppe von Hilfsstoffen sind Polymere. Diese können wasserlöslich oder wasserunlöslich sein und werden als polymere Hilfsstoffe (engl. polymeric excipients, PEx) bezeichnet. Das Umweltverhalten von PEx wird maßgeblich durch ihre biologische Abbaubarkeit bestimmt. Die OECD-301-Screeningtests zur leichten biologischen Abbaubarkeit wurden jedoch ursprünglich nicht für Polymere entwickelt. Daher müssen diese Tests angepasst werden, um ihre Anwendbarkeit auf Polymere auszuweiten. Darüber hinaus müssen die Emissionen während des gesamten Lebenszyklus berücksichtigt werden, um ein umfassendes Bild ihrer Umweltauswirkungen zu erhalten. Diese Dissertation hat zum Ziel, diese Datenlücken zu schließen, und stellt dazu vier sich ergänzende Publikationen (Publikationen 1- 4, P1-4) vor. In diesen Publikationen wurde die biologische Abbaubarkeit und die Auswirkungen von Hilfsstoffen auf den Lebenszyklus systematisch bewertet, wodurch eine Grundlage für das sichere und nachhaltige Design von PEx geschaffen wurde (“Benign-by-Design“, BbD).